Relatively large lenticulo striate arteries penetrate the most ventral portion of the putamen and course through it from ventral to dorsal to supply the basal ganglia and internal capsule. In passing through the putamen the calibre of the vessels reduces from ventral to dorsal and so do the perivascular spaces. The perivascular spaces are in direct communication with the extra cellular fluid in the putamen and arterial pulsations in the lenticulo striate vessels act in cooperation with the peri-vascular spaces to create fluid pumps that drive extra cellular fluid dorsoventrally in the opposite direction to the arterial supply. The extra cellular fluid is cleared into the perivascular spaces with increasing efficiency as one moves from the dorsal to the ventral putamen as a consequence of the increasing calibre of the lenticulo striate vessels.
When delivering a drug by convection enhanced delivery into the putamen or other regions of the brain to treat conditions such as Parkinson's disease, Huntington's disease or other neurodegenerative disease, it is desirable to fill the greater proportion of the target area with the infused drug. It has been observed that poor volumetric distribution of drug infused, for example, into the putamen down a fine catheter when the tip of the catheter is in close proximity to large calibre lenticulo striate vessels in the ventral portion of the putamen. This is due to a higher rate of clearance of extra cellular fluid and thus drug in the ventral portion of the putamen than there is in its dorsal portion as a consequence of the large calibre perivascular pumps.
Catheters or cannulae have previously been passed into regions of the brain, such as the putamen, for the delivery of drugs (or transplanted cells) through a frontal burr hole at an angle of approximately 45° to the anterior commissure-posterior commissure plane. The disadvantage of this trajectory is that, in order to place an adequate length of the catheter or cannula within the putamen the frontal entry point in the skull needs to be very close to the mid sagittal plane because of the orientation of the putamen which angles laterally from its anterior to posterior aspect. The putamen also angles from medial to lateral in the vertical or coronal plane from its dorsal to ventral aspect. A frontal entry point close to the mid sagittal plane increases the risk of causing haemorrhage because the calibre and density of the veins draining the cortex into the sagittal sinus increase as they approach the midline. The putamen is bean shaped with a concavity on its medial aspect and is tapered at its posterior end. A trajectory entering its most dorsal portion and passing at 45° into it will result in a relatively short catheter length contained within the putamen if the distal end of the catheter is to remain within the structure. The short length of catheter that is within the structure limits the volume of drug that can be infused into the putamen as there is a tendency for the drug to reflux along the length of the catheter, generally giving an elongate infusion volume. As described above, the clearance of extracellular fluid and therefore of the infused drug will be greatest in the most ventral portion of putamen where the enlarged perivascular spaces act as fluid sumps. This will limit the distribution of the drug into the more dorsal aspects of the structure. An additional disadvantage of the above described trajectory is that the distal end of the catheter will be passing into a portion of the putamen which is densely supplied by large calibre lenticulo striate vessels and therefore the risk of haemorrhage is increased.
Particular problems associated with delivering infusate to the putamen of rhesus and cynomolgous monkeys were described in Brady et al. 2013, which measured the loss of volume due to overflow, perivascular flow, backflow and catheter tract leakage. Brady carried out infusions using catheters inserted from a superior position, which is the commonly accepted approach to target structures in the brain (as described in Slevin et al. 2005). However, Brady notes that an axial catheter trajectory passing through the frontal sinuses, although not commonly used due to technical difficulties in implanting catheters through this structure and the risk of infection when traversing the mucosa lined sinus, may have a geometric advantage due to the catheter being inserted along the long axis of the putamen.
In view of the problems associated with delivering fluid to the brain there is a need to provide improved methods for this delivery.